The emerging evidence for the involvement of G-quadruplex structures in cellular processes such as transcription control of c-MYC has stimulated the development of drugs that have selectivity between different G-quadruplex structures. G-quadruplexes are intramolecular complexes formed in the presence of large numbers of guanines in a small region of DNA. The promoter regions of some important genes such as the insulin, c-MYC, PDGF, HER-2/neu, and c-MYB genes, human and chicken β-globin genes, rat preproinsulin II gene, adenovirus serotype 2 and retinoblastoma susceptibility genes have been found to contain G-rich sequences that have the ability to form G-quadruplex structures under physiological conditions. To date, the involvement of these quadruplex structures in transcription control has been shown only for the insulin gene and the c-MYC gene. Due to the structural polymorphism in G-quadruplex structures, different G-quadruplex topologies are associated with different signaling pathways.
There are at least three proposed conformations of G-quadruplexes. These are basket type, propeller type, and chair type. (See FIGS. 1A–1C.) One type G-quadruplex structures is believed to be present in the human telomeric sequence and inhibits telomerase activity by sequestration of the substrate required for enzyme activity. (Telomerase is involved in telomere maintenance in tumor cells; inhibition leads to the telomere shortening and senescence.)
On the other hand, another type G-quadruplex is found in the control regions of the c-MYC gene and the formation of this type of G-quadruplex inhibits transcription. This is significant because overexpression of c-MYC results in increased cellular proliferation in many malignancies including breast, colon, cervix, small cell lung cancer, osteosarcomas, glioblastomas and myeloid leukemias. The nuclease hypersensitivity element (NHE) III1 upstream of the P1 promoter of c-MYC controls up to 85–90% of the transcriptional activation of this gene.
It has been shown that c-MYC transcription can be controlled by stabilizing the relevant G-quadruplex through interaction with the cationic porphyrin TMPyP4. (FIG. 2A.) TMPyP4 stabilizes the G-quadruplex structure with some, but far from perfect, selectivity.
Various cationic porphyrins bind to and stabilize different types of G-quadruplexes, and in some cases facilitate G-quadruplex formation. TMPyP4 also associates with the intramolecular G-quadruplex formed in the human telomeric sequence and this association results in telomerase inhibition. It would be desirable to develop drugs that can differentiate between different types of G-quadruplexes structures for achieving therapeutic selectivity.
Another goal is to provide compounds that associate with G-quadruplexes but which lack the photoinduced cytotoxicity of the porphyrins. It has been shown that substituting selenium for nitrogen in the porphyrin core can eliminate this photocytotoxicity. See Stilts, C. E., et al., J. Med. Chem. (2000) 43:2403–2410 and Hilmey, D. G., et al., J. Med. Chem. (2002) 45:449–461.
The invention is designed to provide non-photocytotoxic compounds that associate selectively with the type of G-quadruplex that characterizes c-MYC.